This proposal is designed to investigate the relationship between lipid solubility and local anesthetic inhibition of sodium channel function. It constitutes a revision of an approved renewal of NIH Grant #GM22113. A hypothesis is presented with the following features. The neutral form of local anesthetics is proposed to participate in conduction block by an action on the nerve membrane lipid bilayer, adding to the blocking action of the cation at a more structured site near the membrane hydrophilic surface. The site occupied by the neutral form resembles that occupied by volatile general anesthetic agents. The membrane lipid bilayer is proposed as a site important to sodium channel block by neutral drugs. Barbiturates are to be included in the hypothesis. Transmembrane potential may alter both general and local anesthetic membrane affinity. Tests of this hypothesis will be made by comparing local and general anesthetic effects on sodium channels; examining the relationship between lipid structural changes and conduction block and determining membrane-buffer partition coefficients. The molecular correlates of drug channel blocking properties such as frequency-dependent conduction block and potency will be pursued. The effects of axoplasmic pH changes on drug properties will be investigated. Methods to be used include examination of sodium currents in the voltage-clamped node of Ranvier and electron paramagnetic resonance spectroscopy of spin-labeled membranes. The results will be of significance with respect to the role of membrane lipids in sodium channel gating. In addition, they will clarify the actions of three classes of agents whose clinical uses include general anesthesia, peripheral nerve and spinal cord conduction block, prevention of cardiac arrhythmias, and anticonvulsant activity.